Glioblastoma stem cells therapy

 描述(申请人提供)：胶质瘤约占所有原发中枢神经系统肿瘤的60%。胶质母细胞瘤(GBM)或IV级胶质瘤是恶性程度最高的肿瘤，占所有胶质瘤的51.2%。胶质母细胞瘤是高度异质性的肿瘤，肿瘤内不同类型的肿瘤细胞和间质细胞之间存在复杂的相互作用。最近的研究表明，大多数肿瘤细胞没有能力重塑原始肿瘤的表型，只有肿瘤中一小部分神经干细胞具有这种能力，称为胶质瘤干细胞(GSCs；也称为肿瘤启动细胞)。 在裸鼠体内进行异种移植。与分化的癌症干细胞相比，这些癌症干细胞似乎对传统疗法更具抵抗力。根据目前对高级别胶质瘤的治疗，大多数患者在一年内死于在切除区域一厘米内形成的新的继发性肿瘤灶。这些病灶富含GSCs，很可能是肿瘤复发的原因。一种新兴的癌症治疗方法是利用肿瘤细胞的生化变化。肿瘤(包括基底膜)表现出特别高水平的氧化应激，通常是由于活性氧(ROS)产生的增加或细胞内ROS清除剂的减少引起的。这种ROS的显著增加被认为促进了细胞的存活并产生了对治疗的抵抗力。鉴于正常细胞和肿瘤细胞的氧化还原状态不同，人们认为后者对其清除ROS的能力有更大的依赖。因此，氧化应激的进一步增加可以压倒肿瘤细胞中的这种应激反应，导致细胞死亡。另一方面，胶质瘤干细胞的代谢状态明显低于非致瘤干细胞，这些细胞维持着低水平的ROS，这是它们自我更新所必需的。通过高通量筛选，我们确定了天然化合物牛津酮通过诱导高水平的细胞内ROS来杀伤胶质瘤细胞。我们假设这种ROS诱导的小分子可以同时靶向GBM细胞和GSCs并杀死它们。在这项建议中，我们将在不同的基底膜和GSCs培养以及不同的GSCs颅内模型中验证该化合物。

 DESCRIPTION (provided by applicant): Gliomas account for about 60% of all primary CNS tumors. Glioblastoma (GBM) or grade IV glioma which comprise 51.2% of all gliomas is the most malignant form. Glioblastoma tumors are highly heterogeneous and there is a complex interaction among different types of tumor cells and stromal cells within the tumor. Recently it has been shown that the majority of tumor cells do not have the capacity to recapitulate a phenocopy of the original tumor and that only a small subpopulation of neural stem-like cells in the tumor, called glioma stem cells (GSCs; also known as tumor initiating cells), have that ability upon xenotransplantation in nude mice. These cancer stem cells appear to be more resistant to conventional therapy as compared to their differentiated counterparts. Following current therapy for high-grade glioma tumors, most patients die within a year from a new secondary tumor foci forming within one centimeter of the resected area. These foci are enriched for GSCs, and it is likely that they are responsible for tumor recurrence. An emerging cancer therapeutic approach is to exploit the biochemical changes in tumor cells. Tumors (including GBM) present particularly high levels of oxidative stress, generally caused by an increase in reactive oxygen species (ROS) production or decrease in intracellular ROS-scavengers. This marked increase in ROS is believed to promote cell survival and confer resistance to therapy. Given this different redox state between normal and tumor cells, it is believed that the latter has a greater reliance on their ROS-scavenging capacities. Thus, further increase in oxidative stress can overwhelm this stress response in tumor cells leading to cell death. On the other hand, glioma stem cells have substantially lower metabolic state than their nontumorigenic counterparts and these cells maintain low levels of ROS, essential for their self-renewal. Through high-throughput screening, we identified the natural compounds obtusaquinone to kill glioma cells by inducing high levels of intracellular ROS. We hypothesize that this ROS-inducing small molecule could target both GBM cells as well as GSCs and kill them. In this proposal, we will validate this compound on different GBM and GSCs in culture and in different GSCs intracranial models.